The Portland cohort study of 24,000 women was completed in 2001 but specimen testing and data analyses are only recently reaching completion. We showed that the most important types of HPV, called HPV16 and HPV18, predict much higher absolute risks of cervical cancer and precancer in prospective follow-up, despite screening, than other carcinogenic HPV types. As a follow-up to our finding, we are extending the length of the follow-up to 16 years, and testing all cases of precancer and cancer for the full range of HPV types.More recent large prospective projects include the ALTS clinical trial and the Guanacaste cohort analyses, both in the testing and analyses phases. The final analyses are still underway for the ALTS trial of 5,000 women with abnormal cytology followed for 2 years. Based on HPV typing of all 20,000 specimens from these participants, we are examining the diverse natural histories of the carcinogenic and non-carcinogenic HPV types, and the influences of co-factors. We are interested in all projects in determining the strength of the relationship between viral persistence and precancer diagnosis. Many data analyses are underway for the Guanacaste Project, for example: 1) All aspects of HPV DNA, cytology, and visual appearance of the cervix among the 10,000 women during the 7 years of follow-up, 2) Examining the relationship of cervical immune profiles and the development of high-grade cervical neoplasia, 4) HPV type variants and risk of viral persistence and progression, and 5) The acquisition of sexually transmitted infections and the onset of cervicitis after sexual debut. We are finding that multiple infections, though very common, show little evidence of synergy or antagonism with regard to either persistence or neoplastic progression. There are several ancillary projects just completed as part of our investigations in Guanacaste. For example, there is a study called the Cervical Immunity Study of 300 women who either exited the Guanacaste Study with oncogenic HPV infection or had newly identified CIN2+ within Guanacaste. The primary goal of the study is to examine the relationships of cervical immunity to HPV clearance, persistence, and the development of CIN2+. Another study is examining HPV infection among older women. A third examines the fluctuations of cervical immunity throughout the menstrual cycle. A fourth examines viral and host genetic variation. Projects to identify immune genes and the role that innate immunity plays in HPV infection and progression to cervical neoplasia are being sought. Research continues on identifying and validating biomarkers of risk of progression is being conducted. This includes the identification of novel tumor suppressor genes found to be methylated in cervical neoplasia. A study called SUCCEED is focused on the identification of biomarkers of risk at each progressive disease stage, aimed to identify the molecular events that are necessary and sufficient for progression to cervical cancer. Frozen specimens, often multiple, from 1500 women with varying grades of cervical neoplasia (including the ectocervix, transformation zone, and endocervix) have already been collected. Most recently, we have launched an effort to validate HPV testing via self-sampling in the Mississippi Delta, a region with relatively high rates of cervical cancer. The project will investigate whether HPV screening might improve screening coverage and accuracy compared with conventional clinic-based cytology. Our newest cohort study will be based on follow-up of 30,000 or more women who are found to be HPV DNA-positive during screening at Kaiser Northern California. Finally, we are working on sharing the longitudinal data from NCI projects with collaborators for research and teaching, using a novel multi-media database system developed with engineers at the National Library of Medicine. Each study area in the HPV Research Unit is directed by a different investigator with specialized expertise.